Epidural Electrical Stimulation Research Articles

Lumbar epidural electrical stimulation enhances respiration in mice

Spinal cord epidural electrical stimulation (EES) has emerged as a novel approach to modulate and interrogate the neural circuit(s) underlying sensorimotor functions in the past few decades. Recent studies have revealed that cervical EES can regulate respiration in both human subjects and animal models. Furthermore, coupled cervical and lumbar stimulations significantly increased the rhythmic motor outputs in both the cervical and lumbar spinal cord. We hypothesize that the lumbar and cervical coupling is underpinned by cervico-lumbar synaptic connections, and thus, EES at level of the lumbar spinal cord alone may also facilitate respiration via the cervico-lumbar circuit. In this study, we applied EES to the dorsal surface of the lumbar spinal cord between levels 1 and 6 (L1-6) in anesthetized mice. We found that rostral lumbar (L1-2) EES at a stimulation intensity of 0.5 mA elicited significantly higher respiratory frequency, tidal volume, and minute ventilation responses compared to the other lumbar levels (L3-4 and L5-6) tested at intensities ranging from 0.1-1.0 mA. The increased respiratory activity elicited by lumbar stimulation persisted even after the stimulation ceased. Using the optimal stimulation parameters that we identified, we further investigated the underlying mechanism of the lumbar EES-induced respiratory response by examining the neuronal activation patterns. Using immunostaining, we detected c-fos signals, a marker of neuronal activity, in the cervical spinal cord and brainstem after EES at L1-2 using 0.5 mA at 30Hz. This indicates that focal lumbar stimulation elicits remote neuronal activation in cervical spinal cord and brainstem, regions that contain respiration-related neural circuits. These findings suggest that lumbar EES may facilitate respiration by recruiting paraspinal respiratory circuits and potentially supra-spinal respiratory central pattern generator(s). This study provides insights into the development of novel approaches to restore normal respiratory patterns for patients with respiratory disorders, particularly spinal cord injuries. This work was supported by The Louis and Harold Price Foundation, H & H Evergreen Foundation, Jonathan and Susan Dolgen Foundation, the National Institute of Drug Abuse (R01DA047637), and the National Institute of Neurological Disorders and Stroke (UH3NS119772) in the National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Functional mapping of the lower urinary tract by epidural electrical stimulation of the spinal cord in decerebrated cat model

Several neurologic diseases including spinal cord injury, Parkinson’s disease or multiple sclerosis are accompanied by disturbances of the lower urinary tract functions. Clinical data indicates that chronic spinal cord stimulation can improve not only motor function but also ability to store urine and control micturition. Decoding the spinal mechanisms that regulate the functioning of detrusor (Detr) and external urethral sphincter (EUS) muscles is essential for effective neuromodulation therapy in patients with disturbances of micturition. In the present work we performed a mapping of Detr and EUS activity by applying epidural electrical stimulation (EES) at different levels of the spinal cord in decerebrated cat model. The study was performed in 5 adult male cats, evoked potentials were generated by EES aiming to recruit various spinal pathways responsible for LUT and hindlimbs control. Recruitment of Detr occurred mainly with stimulation of the lower thoracic and upper lumbar spinal cord (T13-L1 spinal segments). Responses in the EUS, in general, occurred with stimulation of all the studied sites of the spinal cord, however, a pronounced specificity was noted for the lower lumbar/upper sacral sections (L7-S1 spinal segments). These features were confirmed by comparing the normalized values of the slope angles used to approximate the recruitment curve data by the linear regression method. Thus, these findings are in accordance with our previous data obtained in rats and could be used for development of novel site-specific neuromodulation therapeutic approaches.

481 Spinal Cord Stimulator Promotes Neuroplasticity in Patients With Severe Spinal Cord Injury

INTRODUCTION: Traumatic spinal cord injury (SCI) is one of the leading causes of morbidity and mortality worldwide. Recently, epidural electrical stimulation (EES) has been shown to restore voluntary motor control in patients with severe SCI. METHODS: To this date, three patients with SCI have been implanted with 5-6-5-Specify-Medtronic electrodes and Medtronic-Intellis pulse generator. All procedures were approved by the local Ethics Committee. The age of the patients ranged from 38-69 y, and the levels of the SCI were C6-D5. Clinically, they were classified ASIA A (2) or B (1). The time frame after injury was 2-7 y. Intraoperative electrophysiological mapping was performed to ensure correct location of the lead at the levels involved in the control of L3-S2 nerve roots. Clinical assessments were performed every 3 m. Additionally, we measured superficial EMG each month, through sensors equipped with accelerometers and gyroscopes. RESULTS: One patient completed 12 m of intense rehabilitation program. The other two patients are currently on training and to this date they completed respectively 6 and 3 months of the program. All 3 patients were able to perform walking activities on a treadmill and stationary bicycle with stimulation turned on. There was an important improvement in the scales related to motor skills and balance, at expense of worsening in pain scores. After 8 months the first patient started to present voluntary movements even with stimulation turned off. CONCLUSIONS: EES allows restoration of voluntary motor control of the legs after severe traumatic SCI. Moreover, after 8 months, a plastic effect could be observed, and a patient was able to control movements even with off stimulation. The observed improvement in overall patient’s performance occurred at expense of more pain, which need to be addressed carefully.

Improvement of Functional State of Patients after Spinal Cord Injury During Epidural Electrical Stimulation: Prospective Study

the lack of convincing evidence of a therapeutic effect.
 AIM. To evaluate the effect of complex rehabilitation using EPS and activation of the proprioceptive apparatus on the indicators of the functional state of patients with long-term consequences of spinal cord injury with partial spinal cord injury.
 MATERIALS AND METHODS. A prospective study was conducted with the participation of 29 patients with long-term consequences of spinal cord injury with partial spinal cord injury. The catamnesis of the disease was 3.7 ± 0.5 years. Comprehensive rehabilitation included epidural electrical stimulation by implantable electrode and activation of the proprioceptive apparatus. The neurological (ASIA scale) and functional (CSIM III scale) status of the patient was analyzed. Motor function was evaluated using 10-meter Walk test; M-responses of limb muscles — using electromyography, temperature and pain sensitivity — using esthesiometry.
 RESULTS. An increase in muscle strength and M-response of the muscles of the extremities, normalization of the motor deficit index, reduction of the walking test time, increase in movement speed and the patient’s independence index were revealed. There is an improvement in temperature and pain sensitivity at the level of damage and in the dermatomes located distally. The effect decreases in dermatomes far from the level of the electrode installation; but with increase in the number of courses the effect increases.
 DISCUSSION. The results obtained indicate that this rehabilitation complex, including UES, has a positive effect on the functioning of both the motor and sensitive spheres.
 CONCLUSION. Application of EES and activation of the proprioceptive apparatus improves the functional condition of sensorimotor sphere in the long-term consequences of spinal cord injury with partial spinal cord damage. Repeated rehabilitation courses have cumulative effect.

Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury

The neural signals produced by varying electrical stimulation parameters lead to characteristic neural circuit responses. However, the characteristics of neural circuits reconstructed by electrical signals remain poorly understood, which greatly limits the application of such electrical neuromodulation techniques for the treatment of spinal cord injury. Here, we develop a dual electrical stimulation system that combines epidural electrical and muscle stimulation to mimic feedforward and feedback electrical signals in spinal sensorimotor circuits. We demonstrate that a stimulus frequency of 10−20 Hz under dual stimulation conditions is required for structural and functional reconstruction of spinal sensorimotor circuits, which not only activates genes associated with axonal regeneration of motoneurons, but also improves the excitability of spinal neurons. Overall, the results provide insights into neural signal decoding during spinal sensorimotor circuit reconstruction, suggesting that the combination of epidural electrical and muscle stimulation is a promising method for the treatment of spinal cord injury.

Recovery of Volitional Motor Control and Overground Walking in Participants With Chronic Clinically Motor Complete Spinal Cord Injury: Restoration of Rehabilitative Function With Epidural Spinal Stimulation (RESTORES) Trial-A Preliminary Study.

Spinal cord injury (SCI) is damage to any part of the spinal cord resulting in paralysis, bowel and/or bladder incontinence, and loss of sensation and other bodily functions. Current treatments for chronic SCI are focused on managing symptoms and preventing further damage to the spinal cord with limited neuro-restorative interventions. Recent research and independent clinical trials of spinal cord stimulation (SCS) or intensive neuro-rehabilitation including neuro-robotics in participants with SCI have suggested potential malleability of the neuronal networks for neurological recovery. We hypothesize that epidural electrical stimulation (EES) delivered via SCS in conjunction with mental imagery practice and robotic neuro-rehabilitation can synergistically improve volitional motor function below the level of injury in participants with chronic clinically motor-complete SCI. In our pilot clinical RESTORES trial (RESToration Of Rehabilitative function with Epidural spinal Stimulation), we investigate the feasibility of this combined multi-modal approach in restoring volitional motor control and achieving independent overground locomotion in participants with chronic motor complete thoracic SCI. Secondary aims are to assess the safety of this combination therapy including the off-label SCS usage as well as improving functional outcome measures. To our knowledge, this is the first clinical trial that investigates the combined impact of this multi-modal EES and rehabilitation strategy in participants with chronic motor complete SCI. Two participants with chronic motor-complete thoracic SCI were recruited for this pilot trial. Both participants have successfully regained volitional motor control below their level of SCI injury and achieved independent overground walking within a month of post-operative stimulation and rehabilitation. There were no adverse events noted in our trial and there was an improvement in post-operative truncal stability score. Results from this pilot study demonstrates the feasibility of combining EES, mental imagery practice and robotic rehabilitation in improving volitional motor control below level of SCI injury and restoring independent overground walking for participants with chronic motor-complete SCI. Our team believes that this provides very exciting promise in a field currently devoid of disease-modifying therapies.

The Effect of Epidural Electrical Stimulation Application in Individuals with Spinal Cord Injury

Spinal cord injury (SCI) is a significant cause of disability, affecting both children and adults worldwide. These injuries can arise from various conditions, including traumatic, vascular, tumor-related, infection-related, inflammatory (such as multiple sclerosis), or neurodegenerative (like motor neuron disease) origins. Among these, traumatic spinal cord injuries caused by reasons like falls and traffic accidents stand out, particularly in developed countries. Epidural electrical stimulation (EES) was initially used to inhibit chronic pain. Subsequent studies have shown its effectiveness in individuals with SCI. In research spanning from the past to the present, EES applications have been utilized for activities such as motor function improvement, sensory enhancement, bowel functions, increased sexual functionality, and regulating heart rhythms in people with SCI. However, the exact impact of EES remains inconclusive at present and is still a subject of debate.

Consecutive Transcutaneous and Epidural Spinal Cord Neuromodulation to Modify Clinical Complete Paralysis—the Proof of Concept

ObjectiveTo evaluate the effect of transcutaneous (tSCS) and epidural electrical spinal cord stimulation (EES) in facilitating volitional movements, balance, and nonmotor functions, in this observational study, tSCS and EES were consecutively tested in 2 participants with motor complete spinal cord injury (SCI). Participants and MethodsTwo participants (a 48-year-old woman and a 28-year-old man), both classified as motor complete spinal injury, were enrolled in the study. Both participants went through a unified protocol, such as an initial electrophysiological assessment of neural connectivity, consecutive tSCS and EES combined with 8 wks of motor training with electromyography (EMG) and kinematic evaluation. The study was conducted from May 1, 2019, to December 31, 2021. ResultsIn both participants, tSCS reported a minimal improvement in voluntary movements still essential to start tSCS-enabled rehabilitation. Compared with tSCS, following EES showed immediate improvement in voluntary movements, whereas tSCS was more effective in improving balance and posture. Continuous improvement in nonmotor functions was found during tSCS-enabled and then during EES-enabled motor training. ConclusionResults report a significant difference in the effect of tSCS and EES on the recovery of neurologic functions and support consecutive tSCS and EES applications as a potential therapy for SCI. The proposed approach may help in selecting patients with SCI responsive to neuromodulation. It would also help initiate neuromodulation and rehabilitation therapy early, particularly for motor complete SCI with minimal effect from conventional rehabilitation.

Epidural combined optical and electrical stimulation induces high-specificity activation of target muscles in spinal cord injured rats.

Epidural electrical stimulation (EES) has been shown to improve motor dysfunction after spinal cord injury (SCI) by activating residual locomotor neural networks. However, the stimulation current often spreads excessively, leading to activation of non-target muscles and reducing the accuracy of stimulation regulation. Near-infrared nerve stimulation (nINS) was combined with EES to explore its regulatory effect on lower limb muscle activity in spinal-cord-transected rats. In this study, stimulation electrodes were implanted into the rats' L3-L6 spinal cord segment with T8 cord transected. Firstly, a series of EES parameters (0.2-0.6 mA and 20-60 Hz) were tested to determine those that specifically regulate the tibialis anterior (TA) and medial gastrocnemius (MG). Subsequently, to determine the effect of combined optical and electrical stimulation, near-infrared laser with a wavelength of 808 nm was used to irradiate the L3-L6 spinal cord segment while EES was performed. The amplitude of electromyography (EMG), the specific activation intensity of the target muscle, and the minimum stimulus current intensity to induce joint movement (motor threshold) under a series of optical stimulation parameters (power: 0.0-2.0 W; pulse width: 0-10 ms) were investigated and analyzed. EES stimulation with 40 Hz at the L3 and L6 spinal cord segments specifically activated TA and MG, respectively. High stimulation intensity (>2 × motor threshold) activated non-target muscles, while low stimulation frequency (<20 Hz) produced intermittent contraction. Compared to electrical stimulation alone (0.577 ± 0.081 mV), the combined stimulation strategy could induce stronger EMG amplitude of MG (1.426 ± 0.365 mV) after spinal cord injury (p < 0.01). The combined application of nINS effectively decreased the EES-induced motor threshold of MG (from 0.237 ± 0.001 mA to 0.166 ± 0.028 mA, p < 0.001). Additionally, the pulse width (PW) of nINS had a slight impact on the regulation of muscle activity. The EMG amplitude of MG only increased by ~70% (from 3.978 ± 0.240 mV to 6.753 ± 0.263 mV) when the PW increased by 10-fold (from 1 to 10 ms). The study demonstrates the feasibility of epidural combined electrical and optical stimulation for highly specific regulation of muscle activity after SCI, and provides a new strategy for improving motor dysfunction caused by SCI.

94. Subthreshold epidural electrical stimulation induced regeneration and motor recovery following spinal cord injury

94. Subthreshold epidural electrical stimulation induced regeneration and motor recovery following spinal cord injury

Hormonal computing: a conceptual approach.

This paper provides a conceptual roadmap for the use of hormonal bioinspired models in a broad range of AI, neuroengineering, or computational systems. The functional signaling nature of hormones provides an example of a reliable multidimensional information management system that can solve parallel multitasks. Two existing examples of hormonal computing bioinspired possibilities are shortly reviewed, and two novel approaches are introduced, with a special emphasis on what researchers propose as hormonal computing for neurorehabilitation in patients with complete spinal cord injuries. They extend the use of epidural electrical stimulation (EES) by applying sequential stimulations to limbs through prostheses. The prostheses include various limb models and are connected to a neurostimulation bus called the central pattern generator (CPG). The CPG bus utilizes hormonal computing principles to coordinate the stimulation of the spinal cord and muscles.

Effectiveness of preoperative thoracic epidural testing strategies: a retrospective comparison of three commonly used testing methods.

Thoracic epidural analgesia (TEA) is a well stablished technique for pain management in major thoracic and abdominal surgeries; however, it has considerable failure rates. Local anesthetic (LA) administration and subsequent assessment of sensory block through physical examination (e.g., decreased temperature perception determined via an LA temperature dissociation test [LATDT]) has been the historical standard for evaluation of thoracic epidural placement. Nevertheless, newer methods to objectively evaluate successful placement have recently been developed, e.g., the epidural electrical stimulation test (EEST) and epidural pressure waveform analysis (EWA). The purpose of this study was to evaluate the effectiveness of preoperative TEA catheter testing (LATDT, EEST, and EWA) on reducing TEA failure. After obtaining an institutional research ethics board approval for a retrospective study, we conducted a single-institution retrospective review on all TEAs performed between January 2016 and December 2021. Patients were assigned to one of four groups based on the performed test method to verify the placement of the TEA catheter: no test, LATDT, EEST, and EWA. A TEA was deemed successful if it provided bilateral dermatomal sensory block to ice test in the postoperative period, and was used for patient analgesia for at least 24hr. One thousand two hundred and forty-one patients submitted to preoperative TEA were included. Twenty-eight patients were excluded. Tested and untested epidurals had failure rates of 3.8% (95% confidence interval [CI], 1.8 to 6.2) and 11.5% (95% CI, 5.2 to 17.1), respectively (P < 0.001). Objective preoperative testing after placement of thoracic epidurals was associated with a reduction in failure rates.

Utilizing Neuromodulation in the Treatment of Spinal Cord Injury: An Assessment of Clinical Trials from the National ClinicalTrials.gov Database

Spinal cord injury (SCI) is responsible for approximately 18,000 trauma cases each year in the United States, often resulting in debilitating motor and autonomic disability. Neuromodulation is a rapidly growing field of interest in the neurosurgical field and has additionally shown promise in the treatment of SCI. This review characterizes all clinical trials to date studying neuromodulation for the treatment of SCI. The ClinicalTrials.gov database was queried using the search terms "neuromodulation" and "spinal cord injury" on ClinicalTrials.gov. Trials were excluded if they were not yet recruiting, suspended, terminated early, or of unknown status. In total, 33 clinical trials were included in this study. Of the 33 trials, 8 were completed and 1 had published results. Most trials studied deficits of motor function (60%) and bladder control (37%). Fourteen studies (42.4%) utilized transcutaneous spinal stimulation, 7 (21.2%) utilized epidural electrical stimulation, and 6 (18.2%) utilized tibial nerve stimulation. There was an uptrend of clinical trials studying SCI indexed on PubMed, which was comparable to the increased number of publications indexed overall (Pearson correlation, P < 0.001). Of these, only 1 study regarding home tibial nerve stimulation for neurogenic bladder had published data, which was performed with no adverse events. Neuromodulation in SCI studies currently assess transcutaneous spinal stimulation, epidural electrical stimulation, and tibial nerve stimulation. There is currently 1 completed study suggesting feasibility of home neuromodulation techniques without adverse events. The results of trials that will be completed in the next few years will help dictate the potential of neuromodulation as a treatment for SCI.

Rare phenomena of central rhythm and pattern generation in a case of complete spinal cord injury

Lumbar central pattern generators (CPGs) control the basic rhythm and coordinate muscle activation underlying hindlimb locomotion in quadrupedal mammals. The existence and function of CPGs in humans have remained controversial. Here, we investigated a case of a male individual with complete thoracic spinal cord injury who presented with a rare form of self-sustained rhythmic spinal myoclonus in the legs and rhythmic activities induced by epidural electrical stimulation (EES). Analysis of muscle activation patterns suggested that the myoclonus tapped into spinal circuits that generate muscle spasms, rather than reflecting locomotor CPG activity as previously thought. The EES-induced patterns were fundamentally different in that they included flexor-extensor and left-right alternations, hallmarks of locomotor CPGs, and showed spontaneous errors in rhythmicity. These motor deletions, with preserved cycle frequency and period when rhythmic activity resumed, were previously reported only in animal studies and suggest a separation between rhythm generation and pattern formation. Spinal myoclonus and the EES-induced activity demonstrate that the human lumbar spinal cord contains distinct mechanisms for generating rhythmic multi-muscle patterns.

ID: 221013 Optimizing Spinal Cord Stimulation Using a Novel Green's Function-Based Generalized Activating Function

Prior work has shown that patient-specific computational modeling and optimization of epidural electrical stimulation (EES) of the spine can be used to rapidly restore locomotion in paraplegics [1]. To this end, Rowald et al. describe a pipeline for generating detailed spine models from medical imaging data. For a given model, electromagnetic field distributions are calculated for the activation of each electrode contact and coupled to electrophysiological simulations of axon populations within each root and rootlet. Optimal exposure conditions for the safe and selective activation of target roots may thus be identified.

Electric Epidural Stimulation of the Spinal Cord of the Decerebrated Rat

Decerebrated animals are often used in experimental neurophysiology to study multilevel physiological processes. The model of a decerebrated cat is traditionally used to study locomotion in acute experiments. We wondered if it would be possible to replace it with electrical epidural stimulation of the spinal cord with a decerebrated rat model. On an acute preparation of 16 Wistar rats decerebrated at the precollicular level, the tonic muscles activity, muscles evoked potentials and the possibility of inducing locomotion during electrical epidural stimulation of the spinal cord, were studied. Histological control of the level of decerebration was performed in 10 rats. Quadrupedal walking was induced in five animals, bipedal hindlimb walking – in one animal; the parameters of the evoked locomotion do not depend on the substantia nigra degree of damage. The tonic activity and the amplitude of the sensory component of the evoked potential of the hindlimb muscles (mm. tibialis anterior and gastrocnemius medialis) depend on the rostrocaudal level of decerebration – they are higher when the substantia nigra is damaged. Thus, the model under consideration makes it possible to successfully study muscle tonic activity and evoked muscle potentials; however, the use of this model in the study of controlled locomotion requires additional research.

Walking naturally after spinal cord injury using a brain–spine interface

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain–spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4–6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

Ventral and dorsal cervical spinal cord electrical epidural stimulation facilitated respiration differently in the presence of opioids in human via different neural circuits

Opioid overdose is one of the leading causes of overdose related deaths in the United States of America, accounting for 70.6% of overdose fatalities in 2019 alone. A leading cause of death among opioid overdoses is respiratory depression. Epidural electrical stimulation (EES) emerges as a novel approach of facilitating rhythmic motor activities such as locomotion and respiration. Previous studies conducted in humans and rodent models demonstrated respiratory augmentations induced by EES delivered to the dorsal cervical spinal cord. Importantly, EES at the dorsal cervical spinal cord opposes opioid-induced respiratory depression in human. To reveal the mechanism underpins how cervical EES modulate the respiratory neural circuit, we conducted this comparative study between dorsal cervical EES to the ventral EES in patients with opioid-induced respiratory suppression or depression. We hypothesize that the ventral cervical EES activates the local motor neuronal pools while the dorsal EES recruits both sensory and motor cervical circuits as well as accesses supraspinal structures such as medulla. We recruited and consented 25 patients who underwent anterior (ventral) cervical spinal cord surgery and compared the effect of ventral cervical EES to to the effect of dorsal cervical ESS in a dataset that we collected from 18 patients undergoing cervical spinal surgery. In the 25 patients, the EES was deliver to the ventral surface of spinal cord ranging from cervical level 3 to 7 (C3 to C7) for no more than 90 seconds at the optimal intensity ranging from 0.5 mA to 5 mA with stimulation frequencies 5 Hz or 30 Hz. In both the dorsal and ventral EES groups, the subjects were anesthetized with low dose or high dose remifentanil that partially or completely depressed voluntary respiration. We observed three main differences between the dorsal and ventral cervical EEST in regulating respiration in the presence of remifentanil. First, dorsal cervical EES induced the resetting of inspiratory rhythm while ventral cervical EES did not. Second, dorsal but not ventral cervical EES induced longer lasting respiratory modulation after the stimulation stopped. Third, dorsal cervical EES induced both frequency and amplitude changes of respiration while ventral cervical EES modulated the amplitude of the respiration more significantly. These observations suggest that the dorsal and ventral cervical EES facilitate respiration via different neural circuits. This work was supported by the National Institute of Drug Abuse in the National Institutes of Health: R01 DA047637, Louis and Harold Price Foundation, H &amp; H Evergreen Foundation, and J. Yang Family Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Closed-loop electrical epidural stimulation restores ipsilesional in-phase diaphragm activity in spontaneously breathing rats after acute C2-hemisection

Epidural electrical stimulation has great promise for recovering many functions after spinal cord injury, including breathing. High-frequency stimulation of the thoracic [DiMarco and Kowalski, 2009] and cervical cord [Gonzalez-Rothi et al. 2017] recovers some phrenic and diaphragm activity. However, open-loop stimulation paradigms induce tonic activity and, thus far, have not elicited recovery of breathing function independent of the stimulation period. We have shown in C2-hemisected rats, closed-loop epidural stimulation (CLES; paced from contralateral diaphragm EMG activity) increases excitability in the respiratory motor network [Malone et al. 2022]; still, the ability of CLES to recover respiratory function following spinal cord injury has not been explored. Here, we hypothesized that CLES can elicit phasic ipsilesional diaphragm activity in C2-hemisected rats without tonic output. To test this, 3-5 month female Sprague-Dawley rats were anesthetized via inhaled isoflurane anesthetic, implanted with stimulating wire electrodes on the dorsal dura at C4 and recording electrodes bilaterally on the diaphragm, and C2-hemisected. After injury, a 15-30 minute recovery to ensure abolishment of ipsilateral diaphragm activity was followed by measurement of spinal motor evoked potentials of the diaphragm, and a baseline recording of diaphragm EMG activity. Biphasic CLES (n=3), set to an amplitude of ¼ the motor threshold, or a sham waiting period (n=3) was delivered for 20 minutes. EMG post processing was done in Spike2 using custom scripts. Stimulated animals received on average 101.8 +/- 22.8 Hz of stimulation during breaths. In stimulated animals, phasic ipsilesional diaphragm EMG activity significantly increased during stimulation (23.7 +/- 1.9 spikes per breath vs 4.32 +/- 1.9 at baseline, p &lt; 0.005). Stimulation did not increase tonic activity of the ipsilesional diaphragm, and ipsilesional diaphragm activity stopped with cessation of stim indicating no spontaneous recovery of activity. Additionally, there was no significant recovery of sham animals during the same period (5.2 +/- 1.9 vs 4.5 +/- 1.9 spikes per breath). Peak EMG activity and modulus of the contralesional diaphragm were significantly elevated from baseline during stimulation (peak value 0.19 +/- 0.015 V vs 0.15 +/- 0.005 V baseline p &lt; 0.05, % change modulus 34.9 +/- 5.9%, p &lt; 0.03). This work represents the first report that CLES can increase phasic diaphragm EMG activity both ipsi- and contralaterally after acute C2-hemisection. Further study is necessary to determine if CLES can elicit similar effects in a chronic model of injury. Additionally, work to determine the mechanism underlying these changes is essential to tailor this therapy for improving breathing function in individuals with spinal cord injury. T32HL134621, R01HL153102, SPARC OT2OD023854 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies

The Fifth Bioelectronic Medicine Summit Hosted by the Feinstein Institutes for Medical Research (Manhasset, NY) and Columbia Engineering (NY, NY) at The Garden City Hotel, Garden City, NY 11530 on October 11-12th, 2022- Bioelectronic Medicine: Today’s Tools, Tomorrow’s Therapies